Hyperviscosity of blood due to elevated plasma or serum viscosity is associated with serum immunoglobulin abnormalities and is manisfested clinically by a combination of ocular, hematologic, neurologic, cardiovascular, and renal symptoms which are referred to as the hyperviscosity syndrome. This syndrome is a frequent complication in neoplastic plasma cell dyscrasias such as Waldenstrom's macroglobulinemia and multiple myeloma; it has also been observed in hyperplastic connective tissue diseases such as rheumatoid arthritis. In order to further investigate the mechanisms which cause serum hyperviscosity, we propose to continue our studies of the physical, biochemical, and immunochemical properties of some immunoglobulins which are associated with such large increases in serum viscosity that clinical symptoms of the hyperviscosity syndrome are present. Physicochemical methods such as analytical ultracentrifugation, viscometry, solubility studies, circular dichroism, and fluorescence spectroscopy would be used to further analyze the role of protein concentration, molecular size and conformation, and complex formation and aggregation as factors which alter serum or plasma viscosity. For those immunoglobulins which form complexes and high molecular weight aggregates our objectives are to determine: (1) the factors which influence the monomer-polymer equilibria, (2) the nature of the molecular interactions which are responsible for complex formation and aggregation, (3) the location and probable nature of the polymerizing sites, and (4) whether a given complex or aggregate is associated with antibody activity. An additional objective is to investigate the phenomenon of reversible cyroprecipitation, which is often observed in association with serum hyperviscosity. Our broad objectives are to contribute to the fundamental knowledge of (1) the forces that influence the three-dimensional structure of proteins, (2) the relationship between protein structure and physiological/immunological function, and (3) how structural alterations may so disrupt the conformation of biologically active macromolecules that their normal function is impaired and clinical problems ensue.